Nicola L. Barclay

DIURNAL PREFERENCE AND SLEEP QUALITY: SAME GENES? A STUDY OF YOUNG ADULT TWINS

The aims of this study were to examine the genetic and environmental influences on diurnal preference and sleep quality, the association between these phenotypes, the genetic and environmental influences on this association, and the magnitude of overlap between these influences. Using a twin design, data on diurnal preference (measured by the Morningness-Eveningness Questionnaire) and sleep quality (measured by the Pittsburgh Sleep Quality Index) were collected from 420 monozygotic twins, 773 dizygotic twins, and 329 siblings (mode age = 20 yrs, range = 18–27 yrs) from a population-based twin registry across the UK. Univariate analyses indicated that dominance genetic influence accounted for 52% and non-shared environment 48% of variance in diurnal preference. For sleep quality, additive genetic influence explained 43% and non-shared environment 57% of the variance. The bivariate analysis indicated a significant association between greater eveningness preference and poorer sleep quality (r = .27). There was substantial overlap in the additive genetic influences on both phenotypes (rA = .57), and overlap in the dominance genetic influences common to both phenotypes was almost absolute (rD = .99). Overlap in non-shared environment was much smaller (rE = .02). Additive genetic influence accounted for 2% of the association, dominance genetic influence accounted for 94%, and non-shared environmental influences accounted for the remaining 4%. The substantial overlap in genetic influence between these phenotypes indicates that similar genes are important for diurnal preference and sleep quality. Therefore, those genes already known to influence one phenotype may be possible candidates to explore with regards to the other phenotype. (Author correspondence: ps701nh@gold.ac.uk)

Sleep quality and diurnal preference in a sample of young adults: Associations with 5HTTLPR, PER3, and CLOCK 3111†

Research investigating associations between specific genes and individual differences with regards to the quality and timing of sleep has primarily focussed on serotonin‐related and clock genes. However, there are only a few studies of this type and most of those to date have not considered the possibility of gene–environment interaction. Here, we describe associations between sleep quality and diurnal preference and three functional polymorphisms: 5HTTLPR, PERIOD3, and CLOCK 3111. Furthermore, we assessed whether associations between genotypes and sleep phenotypes were moderated by negative life events—a test of gene–environment interaction. DNA from buccal swabs was collected from 947 individuals [mean age = 20.3 years (SD = 1.77), age range = 18–27 years; 61.8% female] and genotyped for the three polymorphisms. Participants completed the Pittsburgh Sleep Quality Index and the Morningness‐Eveningness Questionnaire. There was a significant main effect of 5HTTLPR on sleep quality, indicating that “long–long” homozygotes experienced significantly poorer sleep quality (mean = 6.35, SD = 3.36) than carriers of at least one “short” allele (mean = 5.67, SD = 2.96; β = −0.34, P = 0.005). There were no main effects of 5HTTLPR on diurnal preference; no main effects of PERIOD3 or CLOCK on sleep quality or diurnal preference; and no significant interactions with negative life events. The main effect of the “long” 5HTTLPR allele contradicts previous research, suggesting that perhaps the effects of this gene are heterogeneous in different populations. Failure to replicate previous research in relation to PERIOD3 and CLOCK concurs with previous research suggesting that the effects of these genes are small and may be related to population composition.

Quantitative genetic research on sleep: A review of normal sleep, sleep disturbances and associated emotional, behavioural, and health-related difficulties

Over the past 50 years, well over 100 twin studies have focussed on understanding factors contributing to variability in normal sleep-wake characteristics and sleep disturbances. Whilst we have gained a great deal from these studies, there is still much to be learnt. Twin studies can be used in multiple ways to answer questions beyond simply estimating heritability. This paper provides a comprehensive review of some of the most important findings from twin studies relating to sleep to date, with a focus on studies investigating genetic and environmental influences contributing to i) objective and subjective measures of normal sleep characteristics (e.g., sleep stage organisation, sleep quality); as well as sleep disturbances and disorders such as dyssomnias (e.g., insomnia, narcolepsy) and parasomnias (e.g., sleepwalking, bruxism); ii) the persistence of sleep problems from childhood to adulthood, and the possibility that the aetiological influences on sleep change with age; iii) the associations between sleep disturbances, emotional, behavioural and health-related problems; and iv) processes of gene-environment correlation and interaction. We highlight avenues for further research, emphasising the need to further consider the aetiology of longitudinal associations between sleep disturbances and psychopathology; the genetic and environmental overlap between sleep and numerous phenotypes; and processes of gene-environment interplay and epigenetics.

Associations between sleep quality and anxiety and depression symptoms in a sample of young adult twins and siblings.

OBJECTIVES Little is known about the aetiology of the links between sleep disturbance and anxiety and depression symptoms. The aim of this study was to estimate genetic and environmental influences on these associations. METHODS Questionnaires were completed by 1556 young adults from twin and sibling pairs (61.5% female). RESULTS Sleep disturbance was moderately correlated with symptoms of anxiety (r=.39) and depression (r=.50). There was substantial overlap between genes influencing sleep disturbance and those influencing symptoms of anxiety (rA=.58) and depression (rA=.68). Overall, the associations between sleep and symptoms of both anxiety and depression were mainly due to genes (explaining 74% and 58% of the covariances respectively), with the remainder due to nonshared environmental factors. CONCLUSIONS Moderate phenotypic and genetic correlations between the phenotypes support the view that sleep disturbance is related to the presence of various psychiatric difficulties, but also warrants independent consideration and treatment.

Replication of Genome-Wide Association Studies (GWAS) loci for sleep in the British G1219 cohort

Sleep is a critical behavior shared by most higher animals. Sleep disturbances are comorbid with numerous psychiatric disorders, most notably symptoms of depression. Twin studies have suggested that genetic influences partially underlie the variation seen for numerous sleep‐related traits across individuals. Recently, two Genome‐Wide Association Studies (GWAS) conducted for sleep traits have revealed new candidate genes for sleep‐related measures. We attempted to replicate the two most significant associations from these two studies, CACNA1C (a l‐type calcium channel) with sleep latency and quality and ABCC9 (an ATP‐sensitive potassium channel) with sleep duration, using the G1219 British population sample. We genotyped single‐nucleotide polymorphisms (SNPs) for each of the two different sleep GWAS loci. Linear regression analyses were conducted to assess main effects of these SNPs on their corresponding sleep measures, as well as for depressive symptoms. We successfully replicated an association of a genetic variant in the CACNA1C gene (rs16929277) with sleep quality using an additive model of inheritance. A significant association of the ABCC9 gene (rs11046209) with sleep duration was seen only in a recessive models based upon a rare homozygous genotype (n = 2). There was also a significant association between a different ABCC9 gene variant (rs11046205) and depressive symptoms. These findings add further support for the involvement of calcium channels in the mechanisms regulating sleep function and suggest a possible role of the ABCC9 gene in depression. Copyright

Polymorphisms in the circadian expressed genes PER3 and ARNTL2 are associated with diurnal preference and GNβ3 with sleep measures

Sleep and circadian rhythms are intrinsically linked, with several sleep traits, including sleep timing and duration, influenced by both sleep homeostasis and the circadian phase. Genetic variation in several circadian genes has been associated with diurnal preference (preference in timing of sleep), although there has been limited research on whether they are associated with other sleep measurements. We investigated whether these genetic variations were associated with diurnal preference (Morningness–Eveningness Questionnaire) and various sleep measures, including: the global Pittsburgh Sleep Quality index score; sleep duration; and sleep latency and sleep quality. We genotyped 10 polymorphisms in genes with circadian expression in participants from the G1219 sample (n = 966), a British longitudinal population sample of young adults. We conducted linear regressions using dominant, additive and recessive models of inheritance to test for associations between these polymorphisms and the sleep measures. We found a significant association between diurnal preference and a polymorphism in period homologue 3 (PER3) (P < 0.005, recessive model) and a novel nominally significant association between diurnal preference and a polymorphism in aryl hydrocarbon receptor nuclear translocator‐like 2 (ARNTL2) (P < 0.05, additive model). We found that a polymorphism in guanine nucleotide binding protein beta 3 (GNβ3) was associated significantly with global sleep quality (P < 0.005, recessive model), and that a rare polymorphism in period homologue 2 (PER2) was associated significantly with both sleep duration and quality (P < 0.0005, recessive model). These findings suggest that genes with circadian expression may play a role in regulating both the circadian clock and sleep homeostasis, and highlight the importance of further studies aimed at dissecting the specific roles that circadian genes play in these two interrelated but unique behaviours.

Associations between diurnal preference, sleep quality and externalizing behaviours: a behavioural genetic analysis

BACKGROUND Certain aspects of sleep co-occur with externalizing behaviours in youth, yet little is known about these associations in adults. The present study: (1) examines the associations between diurnal preference (morningness versus eveningness), sleep quality and externalizing behaviours; (2) explores the extent to which genetic and environmental influences are shared between or are unique to these phenotypes; (3) examines the extent to which genetic and environmental influences account for these associations. method: Questionnaires assessing diurnal preference, sleep quality and externalizing behaviours were completed by 1556 young adult twins and siblings. RESULTS A preference for eveningness and poor sleep quality were associated with greater externalizing symptoms [r=0.28 (95% CI 0.23-0.33) and 0.34 (95% CI 0.28-0.39), respectively]. A total of 18% of the genetic influences on externalizing behaviours were shared with diurnal preference and sleep quality and an additional 14% were shared with sleep quality alone. Non-shared environmental influences common to the phenotypes were small (2%). The association between diurnal preference and externalizing behaviours was mostly explained by genetic influences [additive genetic influence (A)=80% (95% CI 0.56-1.01)], as was the association between sleep quality and externalizing behaviours [A=81% (95% CI 0.62-0.99)]. Non-shared environmental (E) influences accounted for the remaining variance for both associations [E=20% (95% CI -0.01 to 0.44) and 19% (95% CI 0.01-0.38), respectively]. CONCLUSIONS A preference for eveningness and poor sleep quality are moderately associated with externalizing behaviours in young adults. There is a moderate amount of shared genetic influences between the phenotypes and genetic influences account for a large proportion of the association between sleep and externalizing behaviours. Further research could focus on identifying specific genetic polymorphisms common to both sleep and externalizing behaviours.

Sleep‐related attentional bias in poor versus good sleepers is independent of affective valence

Contradictory evidence exists relating to the presence of an attention bias to sleep‐related stimuli in poor sleepers/insomnia using the emotional Stroop task (EST). These inconsistencies may be due to methodological issues related to the affective valence of the sleep‐related stimuli. Thus, individuals may attend differentially to sleep‐related stimuli not because of their ‘sleep’ properties, but their negativity. The current study addresses this by controlling the affective valence of sleep‐related words. A total of 107 participants [mean age = 33.22 years, standard deviation (SD) = 12.31 years; 61.7% female] were recruited during an evening event at the Newcastle Science Festival. Participants completed the Pittsburgh Sleep Quality Index (PSQI) and a computerized EST containing 20 non‐affective sleep‐related, 20 neutral and 20 negatively valenced threat words. Good and poor sleepers were categorized using the PSQI. There were no significant differences between groups on response latency to sleep‐related words (t(105) = –0.30, P = 0.76). However, the interaction between good versus poor sleepers and word‐type on response latency was significant (F(2,210) = 3.06, P < 0.05). Poor sleepers took longer to respond to sleep‐related words (mean = 723.35, SD = 172.55) compared to threat words (mean = 694.63, SD = 162.17) than good sleepers (mean = 713.20, SD = 166.32; and mean = 716.65, SD = 181.14). The results demonstrate the presence of an attention bias towards sleep‐related stimuli compared to threat stimuli in poor sleepers. Accordingly, poor sleepers may be consumed by stimuli relevant to their specific difficulties, as well as being more highly attuned to negative cues that signal anxious states. Thus, the present research suggests that there are two opposing forces at play: one which facilitates performance (non‐specific threats) and one which hinders performance (personally relevant threats).

The Genesis 12-19 (G1219) Study: A Twin and Sibling Study of Gene-Environment Interplay and Adolescent Development in the UK

The Genesis 12-19 (G1219) Study is an ongoing longitudinal study of a sample of UK twin pairs, non-twin sibling pairs, and their parents. G1219 was initially designed to examine the role of gene-environment interplay in adolescent depression. However, since then data have continued to be collected from both parents and their offspring into young adulthood. This has allowed for longitudinal analyses of depression and has enabled researchers to investigate multiple phenotypes and to ask questions about intermediate mechanisms. The study has primarily focused on emotional development, particularly depression and anxiety, which have been assessed at multiple levels of analysis (symptoms, cognitions, and relevant environmental experiences). G1219 has also included assessment of a broader range of psychological phenotypes ranging from antisocial behaviors and substance use to sleep difficulties, in addition to multiple aspects of the environment. DNA has also been collected. The first wave of data collection began in the year 1999 and the fifth wave of data collection will be complete before the end of 2012. In this article, we describe the sample, data collection, and measures used. We also summarize some of the key findings to date.

Dependent negative life events and sleep quality: An examination of gene-environment interplay

OBJECTIVES Negative life events are associated with sleep disturbances. Further understanding of these associations is beneficial as sleep disturbances are common. We assessed the association between two commonly distinguished types of negative life events (dependent vs. independent) and sleep quality. The extent to which genetic and environmental influences explained the association between dependent negative life events and sleep quality was also assessed. Finally, we examined the presence of gene-environment interaction by assessing whether genetic liability to sleep disturbance varied as a function of dependent negative life events. METHODS Structural equation modelling was used to perform the statistical analyses on questionnaire data collected from 1556 twin and non-twin siblings. RESULTS Poor sleep quality was more strongly associated with dependent as compared to independent negative life events (r=.34 and .15, respectively). There was substantial overlap in the genetic influences on the association between dependent negative life events and poor sleep quality (rA=.62([.43-.81])), suggesting gene-environment correlation. Environmental overlap was small (rE=.16([.04-.28])). Genetic influences accounted for a large proportion of the association (70%([.47-.92])) with the remaining co-variance due to non-shared environment (30%([.08-.53])). Genetic liability to sleep quality was not moderated by dependent negative life events. CONCLUSIONS Genetic and environmental effects on sleep are not necessarily distinct but to some extent work in concert. This should be considered in future studies assessing the genetic and environmental effects on sleep.